Graft versus host disease (GVHD) is a condition that can develop when immunologically-competent cells have been introduced into an individual, for example during bone marrow or stem cell transplantation. GVHD refers to the immunological process whereby the newly transplanted cells mount a rejection response against host tissue. GVHD can develop after the transplantation or transfusion of bone marrow tissue, haematopoietic stem cells, unirradiated blood products and solid organs containing lymphoid tissue.
There are two types of GVHD, acute and chronic. Acute GVHD develops within the first three months following transplantation and clinical symptoms include dermatitis, enteritis and hepatitis. Chronic GVHD usually develops three months after transplantation and is an autoimmune syndrome affecting multiple organs and tissues, such as the skin, GI tract and liver.
Donor T cells are responsible for triggering the development of GVHD. Donor T cells recognise the host cell antigens as foreign and respond by proliferating and releasing cytokines which in turn may activate cells of the innate immune system.
Allogeneic bone marrow transplantation or haematopoietic cell transplantation remains the most effective curative therapy for the treatment of hematological malignancies, such as leukaemia, myeloma, lymphoma and aplastic anaemia. Severe acute GVHD is the primary cause of mortality and morbidity during bone marrow transplantation. Chronic GVHD can also result in death and survivors are often severely disabled.
Immunosuppressive drugs play a large part in the prevention, therapeutic treatment and management of acute and chronic GVHD. The drugs may be administered to the patient before and after the transplant. Current drugs used in the therapeutic treatment of GVHD include cyclosporine, methotrexate, tacrolimus, sacrolimus, mycophenolate mofetil and steroids. Immunosuppression regimens often involve the administration of a combination of drugs for maximal effect.
Chaperonin 10 (cpn10) is present in a variety of organisms, from bacteria to humans, and is a member of the heat shock family of proteins (chaperones) which are among the most evolutionary stable proteins in existence. The chaperone molecules are involved in post-translational folding, targeting and assembly of other proteins (Hartman et al., 1992, Proc. Natl. Acad. Sci. USA, 89, 3394-8) but do not themselves form part of the final assembled structure (Ellis et al., 1991, Annu. Rev. Biochem. 60, 321-47). These proteins play essential roles in normal cells but their production is upregulated during cellular stress (eg. metabolic disruption, infection, inflammation, transformation).
It was unexpectedly discovered that chaperonin 10 has the same amino acid sequence as Early Pregnancy Factor (EPF) (Morton et al., International Publication WO 95/15338). EPF is a pregnancy-associated substance that appears in the maternal serum within 6-24 hr of fertilization (Morton et al., 1974, Nature, 249; 459-460 and Morton et al., 1976, Proc. R. Soc. Lond., 193; 413-9). It is present for at least the first half of pregnancy and is essential for continued embryonic growth and survival (Morton et al., 1987, Current Topics in Developmental Biology 23; 73-92). It is now clear that EPF has many physiological functions and its production is not confined to pregnancy.
It has been reported that EPF can act as an immunosuppressant, release suppressor factors from lymphocytes (Rolfe et al., 1988, Clin. Exp. Immunol. 73, 219-225) and augment the rosette-inhibiting properties of an immunosuppressive anti-lymphocyte serum (Morton et al., 1974 and 1976, supra). EPF can suppress the delayed-type hypersensitivity reaction to trinitrochlorobenzene in mice (Noonan et al., 1979, Nature, 278, 649-51), suppress mitogen-induced lymphocyte proliferation (Athanasas-Platsis, 1993, PhD Thesis, The University of Queensland) and suppress IFN-γ production by CD4+ T cells.
However, there has been no direct evidence as to whether EPF or cpn10 may have potential as an immunosuppressive agent in transplantation, and in particular in the prevention of GVHD. Chaperonin 60, a related heat shock protein, which can also act as an immunosuppressant, has not been shown to possess any therapeutic effects in GVHD. In fact, the prior art teaches that heat shock proteins may have adverse effects on transplantation (Ogita et al., 2000, Transplantation, 69, 2273-2277).